Trientine, chemically known as triethylenetetramine or N,N′-bis(2-aminoethyl)-1,2-ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson's disease.

Trientine dihydrochloride formulation, developed by Aton with the proprietary name SYPRINE, was approved by USFDA on Nov. 8, 1985 for the treatment of patients with Wilson's disease, who are intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer's disease and cancer.
Various synthetic methods for preparation of triethylenetetramine (TETA) and the corresponding dihydrochloride salt have been disclosed in the prior art.
U.S. Pat. No. 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using Titania supported phosphorous catalyst while U.S. Pat. Nos. 4,550,209 and 5,225,599 disclose catalytic condensation of ethylenediamine and ethylene glycol for the synthesis of linear triethylenetetramine using catalysts like zirconium trimethylene diphosphonate, or metatungstate composites of titanium dioxide and zirconium dioxide.
U.S. Pat. No. 4,503,253 discloses the preparation of triethylenetetramine by reaction of an alkanolamine compound with ammonia and an alkyleneamine having two primary amino groups in the presence of a catalyst, such as supported phosphoric acid wherein the support is comprised of silica, alumina or carbon.
The methods described above for preparation of triethylenetetramine require high temperatures and pressure. Further, due to the various possible side reactions and consequent associated impurities, it is difficult to control the purity of the desired amine.
CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of N,N′-dibenzyl-,N,N′-bis[2-(1,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N′-dibenzyl-,N,N′-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N′-dibenzyl-,N,N′-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.
CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetrahydrochloride salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetrahydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetrahydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.
The process is quite circuitous and cumbersome, requiring use of strong bases, filtration of sodium chloride and results in yields as low as 60%.
U.S. Pat. No. 8,394,992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetrahydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetrahydrochloride salt with a strong base like sodium alkoxide to produce the amine free base (TETA) and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether (TBME), followed by removal of sodium chloride salt and finally the amine free base TETA is treated with hydrochloric acid in solvent ethanol to give trientine hydrochloride salt.
The method suffers from the following drawbacks.                a) Lengthy process comprising treatment of tetrahydrochloride salt with a base in anhydrous conditions to obtain the amine and its further conversion to TETA dihydrochloride, which includes a number of unit operations such as solvent extraction, washing of filtered solid, solvent concentration, crystallization at various stages of synthesis etc.        b) Use of excessive amounts of hydrochloric acid as well as anhydrous alcoholic and ether solvents.        c) Stringent requirement of complete removal of sodium chloride formed during the process. If the salt is not scrupulously removed, the final product, trientine hydrochloride salt is unlikely to pass the sulphated ash test, which is indicative of complete removal of inorganic impurities from the drug product.        
Thus it would be evident that there still exists a need for a convenient, cost effective, and industrially viable process for synthesis of triethylenetetramine dihydrochloride (1) which avoids the following.
a) lengthy synthetic routes for protection and deprotection of the reactant amines and intermediates,
b) excessive use of organic solvents,
c) use of mineral acids in multiple steps
The process further eliminates use of strong bases, as well as controls the number of unit operations, and yet provides the desired dihydrochloride in substantially pure form in good yield.
The present inventors have developed a novel process for synthesis of triethylenetetramine dihydrochloride (1) comprising a single step of treating Boc-protected amine (6) with hydrochloric acid to give the desired dihydrochloride salt (1) in substantially pure form and in good yield.
In this way, the present inventors have developed a convenient and cost-effective process by skillfully manipulating the deprotection, salt formation and isolation steps in the synthesis of desired dihydrochloride (1). The method avoids lengthy synthetic steps, strong bases, excessive use of organic solvents, use of multi-molar equivalents of mineral acid and most significantly eliminates the possibility of traces of inorganic salts in the final product. The use of hydrochloric acid in sub-equimolar quantities for simultaneous deprotection and salt preparation reaction results in selective formation of the dihydrochloride salt.